The invention relates to calcium-strontium-hydroxyphosphate-(strontium-apatite-) cement preparations, which contain calcium and strontium, and to uses thereof. The invention further relates to strontium-apatite cements, which are formed from these cement preparations, and to a process applied for their manufacture. The strontium-apatite is well suitable for medical purposes, in particular as bone substitute materials, with specific suitability for filling bone defects caused by osteoporosis.
The human and animal hard tissue essentially consists of hydroxyapatite, wherein there is mostly no stoichiometric hydroxyapatite, but an apatite structure, in which sodium- (Na), potassium- (K), magnesium- (Mg) and strontium- (Sr) salts are further incorporated.
In addition, carbonate, that is incorporated into the apatite structure by substituting phosphate groups, is further incorporated into the hard tissue.
Physiologically occurring apatite is nanocrystalline, illustrated in the X-ray diffractogram in the form of a band broadening, which does not allow an exact allocation of the apatite structures, as it is rather a superposition of single peaks.
Calcium phosphates are biocompatible and osteoconductive, which means that newly formed bone tissue deposits directly thereon. In addition, they are resorbable, because they are recognized as body-consistent (i.e., the body recognizes them as part of itself) and can be catabolized by specific bone-resorbing cells such as osteoclasts, within the framework of natural bone metabolism and restructuring. During such restructuring processes, calcium phosphates can be catabolized and substituted by endogenous bones.
Calcium phosphate ceramics have been on the market since about 1970. They are predominantly incorporated into the human and animal body in the form of pre-made molded bodies or as granules. These materials proved to be effective in clinical applications, however, they can be incorporated only rarely into defects in a force-fit manner, since the defects are mostly irregular. Failure to provide a force-fit incorporation, however, often results in a washing-out of the granules, or in an in-growth of connective tissue into the defects. This subsequently leads to a failure of augmentation.
Calcium phosphate ceramics are predominantly prepared from hydroxyapatite, whereby these ceramics are not resorbable, or from bi-phasic calcium phosphate ceramics, which consist of varying proportions of β-tricalcium phosphate (β-TCP) and hydroxyapatite and which may be resorbed due to the resorbability of the β-tricalcium phosphate, corresponding to its mass proportion.
Calcium phosphate cements have been mentioned in the literature since 1985. They have advantages over ceramics, because they can be incorporated force-fit into the body (W. E. Brown and L. C. Chow, “A new calcium phosphate, water-setting cement”, Chem. Res. Prog. (1986) 352-379; U.S. Pat. No. 4,612,053; U.S. Pat. No. 5,149,368; U.S. Pat. No. 4,518,430; WO96/14265; EP0835668 A1). These cements are characterized by a calcium/phosphate (Ca/P) ratio of ≧1.5.
By adding carbonate, this ratio can be increased even further. There are contradictory reports about the resorbability of these materials, because such cements can not be resorbed, if the reaction product is hydroxyapatite. Or, if the reaction product is calcium-deficient hydroxyapatite (CDHA), it is resorbable by osteoclasts and can be substituted with new bone by means of osteoblasts. However, the resorption rate is then not predictable, because the resorption is dependent on the cellular activity of the recipient, the local blood flow rate, and the location of the implant.
Such cements have already been successfully introduced into the market (BoneSource® cement, Norian(® SRS® cement, Biobon® cement, Calcibon® cement). A main point of criticism from the user's view, however, is still the unpredictable resorbability. The market demands a product, which ensures a high mechanical stability, and which is eventually completely resorbed. After a certain period of time, the product should be substituted with endogenous bone material. Thus, many manufacturers add soluble minerals such as CaHPO4, CaSO4, CaCO3 or β-TCP to the bone substitute materials, in order to enhance the resorption rate in addition to the passive solubility. However, this solves the problem only partially, because the main component still remains only slightly resorbable or not at all resorbable.
The cement resorption, which is essentially controlled by cellular phenomena, follows the rules of Wolff's Law. Wolff's Law describes the steady bone restructuring conditions, and its main assertion is that bone remains only at locations where it is indeed required from a bio-mechanical point of view. From this assertion, it follows that the pressure strength of an artificial bone substitute material should be directed by that of trabecular bone.
This means that a pressure strength of >40 MPa is not desirable at all, because otherwise a certain “stress-shielding” is generated by the cement, which loosens up the bone structure of the adjacent implant bearing due to the higher strength of the cement. Thereby, the place of the lowest bio-mechanical strength of the cement is shifted to the periphery of the implant bearing, which is not desirable.
The main use of bone substitute materials lies in the filling of metaphysic bone defects and of vertebral bodies. These defects mainly occur during osteoporosis. Osteoporosis is a systemic disease of the whole organism, which is essentially expressed by an imbalance of the bone metabolism. Here, the anabolic and catabolic bone restructuring processes are reversed, and more bone material is decomposed by an osteoclastic activity, than is grown by the osteoblastic activity. Attempts to control this imbalance of bone decomposition rate to bone growth rate have been to deliver various systemically effective substances. These include, inter alia, bisphosphonates and hormone preparations, which however threaten the whole organism. In this respect, a bone substitute material that would be desirable is characterized by not only representing a bone substitute substance or filler, but a material that acts upon the surrounding bone cells in such a way that it reverses the metabolic processes, so that the excessive osteoclastic activity itself is attenuated by the bone substitute material and the osteoblastic activity (the in-growth of bones) is stimulated. The aim is to avoid the development that, once a bone substitute material is incorporated through the osteoblastic activity, it is again rapidly decomposed by the increased osteoclastic activity, without the ability of building up new bone at the same time due to the attenuation of osteoblastic activity caused by osteoporosis.
These problems are not solved when considering the present state of the art. In WO92/02478 A1 a calcium phosphate cement containing strontium ions in the form of SrCO3 is disclosed, however, the strontium carbonate is only used for influencing the expansion properties of the cement which, as a main component, consists of magnesium ammonium phosphate. In addition, this strontium carbonate is dissolved rapidly out of the cement due to its potential solubility, so that no protracting effect can originate therefrom, and thereby the bone metabolism cannot be influenced.
It would therefore be desirable to provide a material, which is particularly suitable as a bone substitute material, particularly for osteoporotic bone.